Molecular manipulation of G-protein-coupled receptors: A new avenue into drug discovery

During the past 10 years or so, associated with the introduction of molecul ar biology techniques to G protein-coupled receptor (GPCR) research, outsta nding progress has been made in understanding the mechanisms of action of t hese key proteins and their physiological functions. in-vivo manipulation o f levels of GPCRs using transgenic and gene knock-out approaches have been particularly successful in assessing the roles of specific GPCRs in animal physiology. Drug discovery is aiming to produce highly specific compounds based on subt le definition of receptor subtypes which can best be studied using heterolo gous expression of wild type or mutated forms of cDNA or genes encoding the se proteins. Furthermore, new therapeutic opportunities may be provided by investigation of orphan receptors, the natural ligands for which remain uni dentified. Some human diseases have been shown to be associated with rare m utations of GPCRs and the possibility that widely distributed polymorphisms in GPCR genes may allow selective therapeutic strategies for population su bgroups is driving the development of the science of pharmacogenetics.